Orlistat (also known as tetrahydrolipstatin (THL) and marketed under the trade name XENICAL ORLISTAT® by Roche; or over-the-counter as ALLI® by GlaxoSmithKline), is a drug designed to treat obesity. Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini. However, due to simplicity and stability, orlistat, rather than lipstatin, was developed as an anti-obesity drug.
Orlistat prevents the absorption of fats from the human diet, thereby reducing caloric intake. Orlistat works by inhibiting pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after an oral dose. The primary route of elimination is through the feces.
The chemical structure of orlistat was originally described in U.S. Pat. No. 4,598,089. Due to its low melting point of about 44° C., orlistat undergoes both hydrolytic and thermal degradation, particularly when stored in a humid atmosphere or above 35° C. in a dry atmosphere. XENICAL ORLISTAT® and ALLI® are sold as granule-filled hard shell capsules. XENICAL ORLISTAT® and ALLI® contain orlistat granulated with microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone and talc. However, solid dosage forms, such as tablets, or dosage forms containing solid fill materials, such as hard gelatin capsules, can be difficult to formulate from a powder mix or by conventional wet granulation methods due to picking and sticking phenomena during tablet compression or encapsulation. Further, granulated or crystalline orlistat is subject to thermal and hydrolytic degradation during both manufacturing and subsequent storage as described above.
In an effort to overcome these difficulties, U.S. Pat. No. 6,004,996 to Shah et al. describes dosage forms containing orlistat-containing particles or pellets having a diameter from 0.25 mm to 2 mm, preferably from 0.5 to 1.5 mm, and a stabilizer. The pellets also preferably contain microcrystalline cellulose. The pellets can be encapsulated in gelatin capsules. Shah alleges that the products are chemically stable; however, Shah provides no data to support this conclusion. Further, all of the pellets are dried at temperatures less than 35° C., which is the temperature above which orlistat begins to degrade. Shah does not disclose or suggest solutions containing orlistat encapsulated in capsules nor does Shah disclose any data related to the dissolution profiles of the formulations.
In addition to the stability problems associated with solid orlistat formulations, administration of orlistat causes several side effects, one of the more severe being oil spotting. This phenomenon reflects the physical separation of liquid unabsorbed dietary fiber from the bulk solids in the lower large intestine. Reformulations of orlistat have been explored in an attempt to alleviate oil spotting. For example, U.S. Pat. No. 6,703,369 to de Smidt et al. describes compositions containing orlistat and at least one fatty acid ester of a polyol, wherein the fatty acid ester has a melting point greater than 37° C. A preferred fatty acid ester of a polyol is a glyceride ester. The mixture of the fatty acid of a polyol and orlistat are co-melted, additional excipients, if any, are added, and the mixture is stirred and cooled until solidification. The solid material is ground and the resulting solid particles are pressed into a tablet or encapsulated in hard shell capsules.
European Patent No. EP 1 399 152 to F. Hoffman-La Roche AG describes compositions containing a lipase inhibitor, preferably orlistat, and a sucrose fatty acids ester, such as a mono-, d-, tri-, or tetraester. The mixture of the lipase inhibitor and the sucrose fatty acid ester is a solid material as shown in the examples, not a solution. For example, Example 9 describes encapsulating pellets containing orlistat and sucrose palmitate in gelatin capsules.
European Patent No. EP 1 399 153 to F. Hoffman-La Roche AG describes compositions containing orlistat and a fatty acid or fatty acid salt or mixtures thereof. The compositions described in the '153 patent are solids at the time of manufacture, not solutions.
European Patent No. EP 1 105 122 to F. Hoffman-La Roche AG describes compositions containing a lipase inhibitor and one or more additives, such as poorly digestible, poorly fermentable, hydrophilic and/or hydrocolloidal food grade thickeners and emulsifiers. The compositions described in the '122 patent are solids at the time of manufacture, not solutions, and are reconstituted to form suspensions (see Example 1).
The art discussed above disclose solid orlistat formulations. As discussed above, it is known in the art that crystalline and granulated orlistat is susceptible to thermal and hydrolytic degradation, particularly at elevated temperatures (e.g., above 35° C.). The art does not provide any data regarding the chemical and/or physical stability of the various solid formulations.
U.S. Patent Application Publication No. 2004/0175420 to de Smidt et al. describes compositions containing at least one lipase inhibitor, such as orlistat, at least one surfactant, and at least one dispersant. Most of the examples in the '420 application describe a solid fill material. Examples 6 and 7 describe what appear to be liquid fills; however, the carriers are polyethylene glycol, glycerol, and polyethylene glycol 40 stearate. As shown in the examples below, formulations containing orlistat dissolved in a mixture of polyethylene glycol 400 and polyethylene glycol 600 solidify upon cooling to form a white solid. Also, polyethylene glycol is incompatible with orlistat, accelerating degradation of the active agent. The '420 application does not disclose or suggest fill materials containing orlistat dissolved in medium chain triglycerides, citrate esters, or combinations thereof. The '420 application does not disclose any data related to the stability of the formulations and/or the release profile of the formulations.
There exists a need for lipase inhibitor-containing fill materials, particularly orlistat-containing liquid fill materials, which are chemically and physically stable over an extended period of time.
Therefore, it is an object of the invention to provide orlistat-containing liquid fill materials which are chemically and physically stable over an extended period of time, and methods of making and using thereof.
It is further an object of the invention to provide orilstat-containing liquid fill materials having a high loading of orlistat, which can reduce the size of the capsule needed and thus improve patient compliance, and methods of making and using thereof.
It is still further an object of the invention to provide orlistat-containing liquid fill materials, in the form of clear solutions, which can be encapsulated in clear, transparent capsules.